On 15 January 2021, the US Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu, Daiichi Sankyo) for adult patients with locally advanced or metastatic HER2-positive gastric or gastro-oesophageal (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
Efficacy was evaluated in a multicentre, open-label, randomised study (DESTINY-Gastric01, NCT03329690) in patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens, including trastuzumab, a fluoropyrimidine- and a platinum-containing chemotherapy. A total of 188 patients were randomised (2:1) to receive fam-trastuzumab deruxtecan-nxki 6.4 mg/kg intravenously every 3 weeks or physician’s choice of either irinotecan or paclitaxel monotherapy.
The main efficacy outcome measures were overall survival (OS) and objective response rate (ORR) assessed by independent central review (RECIST v1.1) in the intent-to-treat population. Additional efficacy outcome measures were progression-free survival (PFS) and duration of response (DoR).
The OS was 12.5 months (95% confidence interval [CI] 9.6, 14.3) in the fam-trastuzumab deruxtecan-nxki arm compared with 8.4 months (95% CI 6.9, 10.7) in the irinotecan or paclitaxel arm (hazard ratio 0.59; 95% CI 0.39, 0.88, p = 0.0097).
Confirmed ORR was 40.5% (95% CI 31.8, 49.6) in the fam-trastuzumab deruxtecan-nxki arm compared with 11.3% (95% CI 4.7, 21.9) for those receiving irinotecan or paclitaxel.
Median PFS was 5.6 months (95% CI 4.3, 6.9) in the fam-trastuzumab deruxtecan-nxki arm compared to median PFS of 3.5 months (95% CI 2.0, 4.3) in the irinotecan or paclitaxel arm.
Median DoR was 11.3 months (95% CI 5.6, NR) vs 3.9 months (95% CI 3.0, 4.9), respectively.
The most common (≥ 20%) adverse reactions including laboratory abnormalities were anaemia, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhoea, hypokalaemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia. The Prescribing Information includes a Boxed Warning to advise health professionals of the risks of interstitial lung disease and embryo-foetal toxicity.
The recommended fam-trastuzumab deruxtecan-nxki dose for gastric cancer is 6.4 mg/kg administered as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
Full prescribing information for Enhertu is available here.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment. The FDA approved this application approximately 6 weeks ahead of the FDA goal date.
This application was granted priority review. Fam-trastuzumab deruxtecan-nxki was granted breakthrough therapy designation and orphan drug designation in gastric cancer.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System.